Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.Genome-wide association studies (GWAS) have identified polymorphism in the Apolipoprotein E gene (APOE) to be the most prominent risk factor for Alzheimer's disease (AD). Compared to individuals homozygous for the APOE3 variant, individuals with the APOE4 variant have a significantly elevated risk of AD. On the other hand, longitudinal studies have shown that the presence of the APOE2 variant reduces the lifetime risk of developing AD by 40 percent. While there has been significant research that has identified the risk-inducing effects of APOE4, the underlying mechanisms by which APOE2 influences AD onset and progression have not been extensively explored. In this study, we utilize an isogenic human induced pluripotent stem cell (hiPSC)-based system to demonstrate that conversion of APOE3 to APOE2 greatly reduced the production of amyloid-beta (Aβ) peptides in hiPSC-derived neural cultures. Mechanistically, analysis of pure populations of neurons and astrocytes derived from these neural cultures revealed that mitigating effects of APOE2 are mediated by cell autonomous and non-autonomous effects. https://www.selleckchem.com/products/tunicamycin.html In particular, we demonstrated the reduction in Aβ is potentially driven by a mechanism related to non-amyloidogenic processing of amyloid precursor protein (APP), suggesting a gain of the protective function of the APOE2 variant. Together, this study provides insights into the risk-modifying effects associated with the APOE2 allele and establishes a platform to probe the mechanisms by which APOE2 enhances neuroprotection against AD.Migraine patients frequently report cognitive symptoms during the different phases of migraine. The most affected cognitive domains are visuospatial abilities, processing speed, attention and executive functions. We explored migraine patients' performance during a visuospatial task and investigated the activity of brain areas involved in visuospatial processing. A functional magnetic resonance imaging (MRI) visuospatial task, including an angle and a colour discrimination paradigm, was administrated to 17 headache-free migraine patients and 16 controls. Correlations between functional MRI abnormalities and subjects' performance, clinical and neuropsychological variables were also investigated. Deficits at visuospatial cognitive tests were present in around 20% of patients. Migraine patients maintained a preserved behavioural performance (reaction time and number of correct responses) during the angle discrimination task, while they performed less correctly in the colour task compared to controls (p?=?0.05).The comparison of angle vs. colour task revealed an increased activity of the right insula, bilateral orbitofrontal cortex and medial frontal gyrus, and decreased activity of the bilateral posterior cingulate cortex in migraine patients compared to controls. In migraine patients, a better performance in the angle task was associated with higher activation of the right insula and orbitofrontal cortex, as well as with decreased activation of the right posterior cingulate cortex. Our results suggest an adaptive functional plasticity that might help migraine patients to overcome impaired visuospatial skills and preserve an adequate performance during a visuospatial task. These compensatory mechanisms seem to take advantage of recruiting brain areas that are commonly involved also in nociception.Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and glutamatergic pathways play key roles in the causes of OCD. However, first-line therapies include cognitive-behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for new treatment is mandatory. This review focuses on the potential effects of cannabidiol (CBD), as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which CBD provides its benefit properties. CBD medication downregulates GSK-3β, the main inhibitor of the WNT/β-catenin pathway. The activation of the WNT/β-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway and circadian rhythms dysregulation in OCD. Future prospective clinical trials could focus on CBD and its different and multiple interactions in OCD.Drug addiction remains a key biomedical challenge facing current neuroscience research. In addition to neural mechanisms, the focus of the vast majority of studies to date, astrocytes have been increasingly recognized as an "accomplice." According to the tripartite synapse model, astrocytes critically regulate nearby pre- and postsynaptic neuronal substrates to craft experience-dependent synaptic plasticity, including synapse formation and elimination. Astrocytes within brain regions that are implicated in drug addiction exhibit dynamic changes in activity upon exposure to cocaine and subsequently undergo adaptive changes themselves during chronic drug exposure. Recent results have identified several key astrocytic signaling pathways that are involved in cocaine-induced synaptic and circuit adaptations. In this review, we provide a brief overview of the role of astrocytes in regulating synaptic transmission and neuronal function, and discuss how cocaine influences these astrocyte-mediated mechanisms to induce persistent synaptic and circuit alterations that promote cocaine seeking and relapse. We also consider the therapeutic potential of targeting astrocytic substrates to ameliorate drug-induced neuroplasticity for behavioral benefits. While primarily focusing on cocaine-induced astrocytic responses, we also include brief discussion of other drugs of abuse where data are available.